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Ashley V Menk, Nicole E Scharping, Dayana B Rivadeneira, Michael J Calderon, McLane J Watson, Deanna Dunstane, Simon C Watkins, Greg M Delgoffe
Despite remarkable responses to cancer immunotherapy in a subset of patients, many patients remain resistant to these therapies. The tumor microenvironment can impose metabolic restrictions on T cell function, creating a resistance mechanism to immunotherapy. We have previously shown tumor-infiltrating T cells succumb to progressive loss of metabolic sufficiency, characterized by repression of mitochondrial activity that cannot be rescued by PD-1 blockade. 4-1BB, a costimulatory molecule highly expressed on exhausted T cells, has been shown to influence metabolic function...
March 6, 2018: Journal of Experimental Medicine
Zhi Cheng, Runhong Wei, Qiuling Ma, Lin Shi, Feng He, Zixiao Shi, Tao Jin, Ronglin Xie, Baofeng Wei, Jing Chen, Hongliang Fang, Xiaolu Han, Jennifer A Rohrs, Paul Bryson, Yarong Liu, Qi-Jing Li, Bo Zhu, Pin Wang
Several recent clinical trials have successfully incorporated a costimulatory domain derived from either CD28 or 4-1BB with the original CD3ζ T cell activating domain to form second-generation chimeric antigen receptors (CARs) that can increase the responsiveness and survival of CAR-engineered T (CAR-T) cells. However, a rigorous assessment of the individual benefits of these costimulatory components relative to the in vivo performance of infused T cells in patients is still lacking. Therefore, we have designed a study that allows us to investigate and compare the impact of different costimulatory signal domains on CAR-T cells in vivo...
February 2, 2018: Molecular Therapy: the Journal of the American Society of Gene Therapy
Stefanie Koristka, Alexandra Kegler, Ralf Bergmann, Claudia Arndt, Anja Feldmann, Susann Albert, Marc Cartellieri, Armin Ehninger, Gerhard Ehninger, Jan Moritz Middeke, Martin Bornhäuser, Marc Schmitz, Jens Pietzsch, Katja Akgün, Tjalf Ziemssen, Jörg Steinbach, Michael P Bachmann
As regulatory T cells (Tregs) play a fundamental role in immune homeostasis their adoptive transfer emerged as a promising treatment strategy for inflammation-related diseases. Preclinical animal models underline the superiority of antigen-specific Tregs compared to polyclonal cells. Here, we applied a modular chimeric antigen receptor (CAR) technology called UniCAR for generation of antigen-specific human Tregs. In contrast to conventional CARs, UniCAR-endowed Tregs are indirectly linked to their target cells via a separate targeting module (TM)...
March 1, 2018: Journal of Autoimmunity
Jang Hwan Cho, Atsushi Okuma, Dalal Al-Rubaye, Ejaj Intisar, Richard P Junghans, Wilson W Wong
Axl is a tyrosine kinase receptor that is commonly overexpressed in many cancers. As such, Axl represents an attractive therapeutic target. The transfer of engineered T cell expressing chimeric antigen receptor (CAR) is an exciting cancer therapeutic approach that shows high efficacy against cancers in clinical trials, especially for B cell malignancies. Furthermore, recently developed synthetic Notch (synNotch) receptor has demonstrated potential in enhancing the specificity of CAR T cell therapy and delivering therapeutic payloads to tumors in an antigen-dependent manner...
March 1, 2018: Scientific Reports
Yuk Pheel Park, Linchun Jin, Katie B Bennett, Dunrui Wang, Kristianna M Fredenburg, Jennifer E Tseng, Lung-Ji Chang, Jianping Huang, Edward K L Chan
OBJECTIVES: In accordance with the Precision Medicine Initiative, new treatment strategies for head and neck squamous cell carcinoma (HNSCC) are needed to yield better therapeutic outcomes. The purpose of this study was to establish and validate chimeric antigen receptor (CAR)-T cells targets in HNSCC. METHODS: Putative CAR-T antigens were identified in The Cancer Genome Atlas database. To validate antigen suitability, quantitative RT-PCR, flow cytometry, and immunofluorescent staining were performed...
March 2018: Oral Oncology
Jorge Augusto Borin Scutti
On the basis of immunological results, it is not in doubt that the immune system is able to recognize and eliminate transformed cells. A plethora of studies have investigated the immune system of patients with cancer and how it is prone to immunosuppression, due in part to the decrease in lymphocyte proliferation and cytotoxic activity. The series of experiments published following the demonstration by Dr Allison's group of the potential effect of anti-cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) paved the way for a new perception in cancer immunotherapy: Immune checkpoints...
February 23, 2018: International Journal of Oncology
Shu-Ni Zhou, Rui-Zhi Ran, Li-Li Tan, Hao Guo
A recombinant co-stimulatory molecule capable of inducing multiple effects on varied immune cells when present in its soluble active form is termed as SA-4-1BBL. It has been reported to influence innate, adaptive, and regulatory immune cells. Recent studies confirmed its engagement with receptor, 4-1BB leading to collection of interleukin-2 (IL-2) that in turn overcomes Treg suppression. Further, a vast number of pre-clinical studies reported its therapeutic efficacy in the form of adjuvant subunit in cancer vaccines...
March 2018: Experimental and Therapeutic Medicine
Nicole A P Lieberman, Kole DeGolier, Kristen Haberthur, Harrison Chinn, Kara W Moyes, Myriam N Bouchlaka, Kirsti L Walker, Christian M Capitini, Courtney A Crane
Recent advances in cellular therapies for patients with cancer, including checkpoint blockade and ex vivo -expanded, tumor-specific T cells, have demonstrated that targeting the immune system is a powerful approach to the elimination of tumor cells. Clinical efforts have also demonstrated limitations, however, including the potential for tumor cell antigenic drift and neoantigen formation, which promote tumor escape and recurrence, as well as rapid onset of T cell exhaustion in vivo . These findings suggest that antigen unrestricted cells, such as natural killer (NK) cells, may be beneficial for use as an alternative to or in combination with T cell based approaches...
2018: Frontiers in Immunology
Yali Han, Chuanyong Liu, Guanhua Li, Juan Li, Xingyan Lv, Huan Shi, Jie Liu, Shuai Liu, Peng Yan, Shuyun Wang, Yuping Sun, Meili Sun
New immunotherapeutic approaches are urgently needed for gastric cancer due to its poor survival and unsatisfactory treatment. Here we applied the humanized chA21 scfv based chimeric antigen receptor (CAR) modified T cells approach to the HER2 overexpressing gastric cancer treatment. The chA21-4-1BBz CAR T cells specifically exerted Th1 skewed cytokine response and efficient cytolysis of HER2 overexpressing human gastric cancer cells in vitro . Both the cytokine production and cytotoxicity levels were correlated with the level of HER2 surface expression by tumor cells...
2018: American Journal of Cancer Research
He Li, Yao Huang, Du-Qing Jiang, Lian-Zhen Cui, Zhou He, Chao Wang, Zhi-Wei Zhang, Hai-Li Zhu, Yong-Mei Ding, Lin-Fang Li, Qiang Li, Hua-Jun Jin, Qi-Jun Qian
Effective control of non-small-cell lung cancer (NSCLC) remains clinically challenging, especially during advanced stages of the disease. This study developed an adoptive T-cell treatment through expression of a chimeric antigen receptor (CAR) to target human epidermal growth factor receptor (EGFR) in NSCLC. We optimized the non-viral piggyBac transposon system to engineer human T cells for the expression of EGFR-CAR, consisting of EGFR scFv, transmembrane domain, and intracellular 4-1BB-CD3ζ signaling domains...
February 7, 2018: Cell Death & Disease
Saisai Li, Zhongfei Tao, Yingxi Xu, Jia Liu, Na An, Ying Wang, Haiyan Xing, Zheng Tian, Kejing Tang, Xiaolong Liao, Qing Rao, Min Wang, Jianxiang Wang
Acute myeloid leukemia (AML) is a kind of a malignant hematologic tumor caused by uncontrolled repopulation of myeloid hematopoietic stem cells (HSCs). Current therapeutic effects for AML patients are unsatisfactory. Especially relapsed and refractory AML still have poor prognosis. T cell modified by chimeric antigen receptor (CAR) is an immunotherapeutic strategy for malignancies, which has a broad developing prospect. Most of AML cells overexpress the myeloid antigen CD33. Therefore, CD33-specific CAR-T cells with different costimulators (CD28, 4-1BB or both, referred to as CD33 28z...
February 6, 2018: Human Gene Therapy
Yuki Kagoya, Shinya Tanaka, Tingxi Guo, Mark Anczurowski, Chung-Hsi Wang, Kayoko Saso, Marcus O Butler, Mark D Minden, Naoto Hirano
The adoptive transfer of T cells engineered with a chimeric antigen receptor (CAR) (hereafter referred to as CAR-T cells) specific for the B lymphocyte antigen CD19 has shown impressive clinical responses in patients with refractory B cell malignancies. However, the therapeutic effects of CAR-T cells that target other malignancies have not yet resulted in significant clinical benefit. Although inefficient tumor trafficking and various immunosuppressive mechanisms can impede CAR-T cell effector responses, the signals delivered by the current CAR constructs may still be insufficient to fully activate antitumor T cell functions...
February 5, 2018: Nature Medicine
Karine Chemin, Daniel Ramsköld, Lina-Marcela Diaz-Gallo, Jessica Herrath, Miranda Houtman, Karolina Tandre, Lars Rönnblom, Anca Catrina, Vivianne Malmström
The presence of the PTPN22 risk allele (1858T) is associated with several autoimmune diseases including rheumatoid arthritis (RA). Despite a number of studies exploring the function of PTPN22 in T cells, the exact impact of the PTPN22 risk allele on T-cell function in humans is still unclear. In this study, using RNA sequencing, we show that, upon TCR-activation, naïve human CD4+ T cells homozygous for the PTPN22 risk allele overexpress a set of genes including CFLAR and 4-1BB, which are important for cytotoxic T-cell differentiation...
January 31, 2018: European Journal of Immunology
Akihiro Hosoi, Kazuyoshi Takeda, Koji Nagaoka, Tamaki Iino, Hirokazu Matsushita, Satoshi Ueha, Shin Aoki, Kouji Matsushima, Masato Kubo, Teppei Morikawa, Kazutaka Kitaura, Ryuji Suzuki, Kazuhiro Kakimi
To facilitate the optimization of cancer immunotherapy lacking immune-related adverse events, we performed TCR repertoire analysis of tumor-infiltrating CD8+ T-cells in B16 melanoma-bearing mice receiving anti-PD-1, anti-CTLA-4, anti-4-1BB, anti-CD4 or a combination of anti-PD-1 and 4-1BB antibodies. Although CD8+ T-cells in the tumor were activated and expanded to a greater or lesser extent by these therapies, tumor growth suppression was achieved only by anti-PD-1, anti-PD-1/4-1BB combined, or by anti-CD4 treatment, but not by anti-CTLA-4 or anti-4-1BB monotherapy...
January 18, 2018: Scientific Reports
Sonia Guedan, Avery D Posey, Carolyn Shaw, Anna Wing, Tong Da, Prachi R Patel, Shannon E McGettigan, Victoria Casado-Medrano, Omkar U Kawalekar, Mireia Uribe-Herranz, Decheng Song, J Joseph Melenhorst, Simon F Lacey, John Scholler, Brian Keith, Regina M Young, Carl H June
Successful tumor eradication by chimeric antigen receptor-expressing (CAR-expressing) T lymphocytes depends on CAR T cell persistence and effector function. We hypothesized that CD4+ and CD8+ T cells may exhibit distinct persistence and effector phenotypes, depending on the identity of specific intracellular signaling domains (ICDs) used to generate the CAR. First, we demonstrate that the ICOS ICD dramatically enhanced the in vivo persistence of CAR-expressing CD4+ T cells that, in turn, increased the persistence of CD8+ T cells expressing either CD28- or 4-1BB-based CARs...
January 11, 2018: JCI Insight
Jinghua Wang, Siyu Chen, Wei Xiao, Wende Li, Liang Wang, Shuo Yang, Weida Wang, Liping Xu, Shuangye Liao, Wenjian Liu, Yang Wang, Nawei Liu, Jianeng Zhang, Xiaojun Xia, Tiebang Kang, Gong Chen, Xiuyu Cai, Han Yang, Xing Zhang, Yue Lu, Penghui Zhou
BACKGROUND: Acute myeloid leukemia (AML) is one of the most common types of adult acute leukemia. Standard chemotherapies can induce complete remission in selected patients; however, a majority of patients eventually relapse and succumb to the disease. Thus, the development of novel therapeutics for AML is urgently needed. Human C-type lectin-like molecule-1 (CLL-1) is a type II transmembrane glycoprotein, and its expression is restricted to myeloid cells and the majority of AML blasts...
January 10, 2018: Journal of Hematology & Oncology
Il-Kyu Choi, Zhe Wang, Qiang Ke, Min Hong, Yu Qian, Xiujuan Zhao, Yuting Liu, Hye-Jung Kim, Jerome Ritz, Harvey Cantor, Klaus Rajewsky, Kai W Wucherpfennig, Baochun Zhang
The B-lymphotropic Epstein-Barr virus (EBV), pandemic in humans, is rapidly controlled on initial infection by T cell surveillance; thereafter, the virus establishes a lifelong latent infection in the host. If surveillance fails, fatal lymphoproliferation and lymphomagenesis ensue. The initial T cell response consists of predominantly CD8+ cytotoxic T cells and a smaller expansion of CD4+ cells. A major approach to treating EBV-associated lymphomas is adoptive transfer of autologous or allogeneic T cells that are stimulated/expanded on EBV-transformed B cells...
January 23, 2018: Proceedings of the National Academy of Sciences of the United States of America
Payal Mittal, Rebecca Abblett, Joseph M Ryan, Adam T Hagymasi, Archibald Agyekum-Yamoah, Julia Svedova, Steven L Reiner, Marie-Clare St Rose, Matthew P Hanley, Anthony T Vella, Adam J Adler
Agonists to the TNF/TNFR costimulatory receptors CD134 (OX40) and CD137 (4-1BB) elicit antitumor immunity. Dual costimulation with anti-CD134 plus anti-CD137 is particularly potent because it programs cytotoxic potential in CD8+ and CD4+ T cells. Cytotoxicity in dual-costimulated CD4 T cells depends on the T-box transcription factor eomesodermin (Eomes), which we report is induced via a mechanism that does not rely on IL-2, in contrast to CD8+ CTL, but rather depends on the CD8 T cell lineage commitment transcription factor Runx3, which supports Eomes expression in mature CD8+ CTLs...
January 5, 2018: Journal of Immunology: Official Journal of the American Association of Immunologists
Todd Bartkowiak, Ashvin R Jaiswal, Casey R Ager, Renee Chin, Chao-Hsien Chen, Pratha Budhani, Midan Ai, Matthew J Reilley, Manu M Sebastian, David S Hong, Michael A Curran
PURPOSE: Agonist antibodies targeting the T cell co-stimulatory receptor 4-1BB (CD137) are among the most effective immunotherapeutic agents across pre-clinical cancer models. In the clinic, however, development of these agents has been hampered by dose-limiting liver toxicity. Lack of knowledge of the mechanisms underlying this toxicity has limited the potential to separate 4-1BB agonist driven tumor immunity from hepatotoxicity. EXPERIMENTAL DESIGN: The capacity of 4-1BB agonist antibodies to induce liver toxicity was investigated in immunocompetent mice, with or without co-administration of checkpoint blockade, via 1) measurement of serum transaminase levels, 2) imaging of liver immune infiltrates, and 3) qualitative and quantitative assessment of liver myeloid and T cells via flow cytometry...
January 4, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Jiayi Yu, Xiaowen Wu, Junya Yan, Huan Yu, Longwen Xu, Zhihong Chi, Xinan Sheng, Lu Si, Chuanliang Cui, Jie Dai, Meng Ma, Tianxiao Xu, Yan Kong, Jun Guo
BACKGROUND: Chimeric antigen receptor (CAR)-engineered T cells have demonstrated promising clinical efficacy in patients with B cell lymphoma. However, the application of CAR-T cell therapy in the treatment of other solid tumors has been limited. We incorporated 4-1BB into the anti-GD2 CAR-T cells to test their cytotoxicity in melanoma in vitro and in vivo. Moreover, we reported the expression of ganglioside GD2 in non-Caucasian melanoma populations for the first time, thus providing a basis for future clinical research...
January 3, 2018: Journal of Hematology & Oncology
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